tbuckley/cabot-search huggingface dataset:
OS02.7.A The role of epilepsy in elderly patients with Glioblastoma: An Austrian multicenter analysis
Authors: M Demetz, C Hecker, A Krigers, J Kerschbaumer, J Pöppe, P Geiger, A Spinello, C J Griessenauer, C Thomé, C Schwartz, C F Freyschlag
Journal: Neuro-Oncology (2022)

Abstract Background Higher age is a significant predictor of poor outcome in glioblastoma multiforme (GBM) patients. Thus, acquisition of a better understanding of additional prognostic factors in these often-frail patients is of utmost importance. Epileptic seizures correlate with improved overall survival (OS) in low-grade gliomas; however, the impact of epilepsy in GBM patients on outcome parameters is poorly defined. Furthermore, persisting epilepsy significantly influences the patients’ quality of life (QoL). This study aims at specifically evaluating the impact of epilepsy in elderly GBM patients. Material and Methods Two Austrian academic neurosurgical centers retrospectively analyzed all elderly (≥65 years) GBM patients with de-novo tumors, who underwent tumor resections between 09/2006 and 07/2021. Epidemiological, histopathological and survival data were gained from patients’ electronic charts and screened for presence of epilepsy preoperatively or during follow-up. Results 391 patients (55% males, 45% females) with a median age at surgery of 73 years (Interquartile Range (IqR) 68.5-77.5) were analyzed. The mean predicted OS was recorded to be 12.4 months (CI95% 10.9-14.0). Median preoperative Modified Rankin Scale (mRS) was 2 (IqR 1-3), and median preoperative Karnofsky performance score was 80 (IqR 60-90). Mean follow-up was 10.4 months (CI95% 9.1-11.6) in our cohort. 95/391 patients (24%) suffered from preoperative epilepsy. 17 (18%) patients still suffered from epilepsy after tumor resection with eight patients who developed new postoperative seizures, and four patients (1.0%) showed a worsening of already preoperatively diagnosed seizures. Major surgery-associated neurological complications included new motor deficits in 29 (7%) and new aphasia in 16 (4%) patients. Logistic regression showed, patients with seizures had significantly lower mRS (OR=0.735 [CI95% 0.563 0.961], p=0.032) and less frequently occipital tumor location (OR=0.347 [CI95% 0.152-0.791], p=0.018). Postoperative epilepsy resulted in significantly prolonged hospitalization after the surgery (OR=2.622[CI95% 1.496-3.979], p=0.009). Survival did not correlate with preoperative epilepsy (p&amp;gt;0.05). However, Cox regression revealed that multifocal tumor location (HR=1.777 [CI95% 1.197-2.639], p=0.025) as well as thalamic involvement (HR=11.121 [CI95% 3.431-36,046], p=0.030) negatively influenced OS. Furthermore, surgery-associated complications shortened OS significantly (HR=1.945 [CI95% 1,296-2,916], p=0.025). Conclusion Even though epilepsy was not found to directly impact survival in elderly GBM patients, we found that surgery led to epilepsy freedom in a significant proportion of our patient cohort, thereby potentially leading to improved QoL. Greatest focus should be set on avoiding any surgery-associated deficits, since these severely influence the OS.
OS05.5.A Glioblastoma-instructed microglia transit to heterogeneous phenotypic states with dendritic cell-like features in patient tumors and patient-derived orthotopic xenografts
Authors: Y A Yabo, Y Pires-Afonso, P M Moreno-Sanchez, A Oudin, T Kaoma, P V Nazarov, A Skupin, S P Niclou, A Michelucci, A Golebiewska
Journal: Neuro-Oncology (2022)

Abstract Background A major contributing factor to Glioblastoma (GBM) development and progression is its ability to evade the immune system by creating an immune-suppressive tumor microenvironment (TME). GBM-associated myeloid cells, including resident microglia, macrophages and other peripheral immune cells are generally geared towards tumor-supportive roles. It is however unclear whether such recruited myeloid cells are phenotypically and functionally identical. Here, we aim to understand the heterogeneity of the GBM TME, using an unbiased, marker-free approach to systematically characterize cell type identities at the molecular and functional levels. Material and Methods We applied single-cell RNA-sequencing, multicolor flow cytometry, immunohistochemical analyses and functional studies to examine the heterogeneous TME instructed by GBM cells. GBM patient-derived orthotopic xenografts (PDOXs) representing different tumor phenotypes were compared to glioma mouse GL261 model and patient tumors. Results We show that PDOX models recapitulate major components of the TME found in human GBM. Human GBM cells reciprocally interact with mouse cells to create a GBM-specific TME. The most prominent transcriptomic adaptations are found in tumor-associated macrophages (TAMs), which are largely of microglial origin. We reveal inter-patient heterogeneity of TAMs and identify key signatures of distinct phenotypic states within the microglia-derived TAMs across distinct GBM landscapes. GBM-educated microglia adapt expression of genes involved in immunosuppression, migration, phagocytosis and antigen presentation, indicating functional cross-talk with GBM cells. We identify novel phenotypic states with astrocytic and endothelial-like features. Identified gene signatures and phenotypic states are confirmed in GBM patient tumor tissue. Finally we show that temozolomide treatment leads to transcriptomic adaptation of not only the GBM tumor cells but also adjacent TME components. Conclusion Our data provide insights into the phenotypic adaptation of the heterogeneous TME instructed by GBM tumor. We confirm a crucial role of microglia in supporting the immunosuppressive TME and show that PDOXs allow to monitor the highly plastic GBM ecosystem and its phenotypic adaptations upon treatment. This work further confirms the clinical relevance of PDOX avatars for testing novel therapeutics including modalities designed to target the myeloid compartment.
PL01.4.A The relationship between neuronal activity and functional network properties in glioma patients
Authors: M L M Zimmermann, L C Breedt, E G Z Centeno, S D Kulik, F A N Santos, C J Stam, M R van Lingen, A Hillebrand, L Douw
Journal: Neuro-Oncology (2022)

Abstract Background Glioma is associated with pathologically high neuronal activity around the tumor, which associates with faster tumor progression in patients. Concurrently, patients with glioma have local and widespread disturbances of the functional brain network as measured with magnetoencephalography (MEG) such as higher network clustering (the extent to which regions connected to a particular area are also connected to each other) and locally altered integrative connectivity (for instance assessed with a centrality measure). How local neuronal activity and nodal network properties relate to each other has yet to be investigated. Material and Methods We obtained eyes-closed resting-state MEG in 95 glioma patients before tumor resection and 57 matched healthy controls (HC). Broadband power (BBP, 0.5-48Hz) was used as a proxy for neuronal activity. The local clustering coefficient (CC) and eigenvector centrality (EC) were calculated for the functional network in the lower frequency bands (delta, theta, alpha). We compared averaged nodal network properties and local BBP between peritumoral (regions partially overlapping with the tumor) and contralateral homologue regions in patients and compared these to averaged values in HC. Linear mixed models were used to relate nodal CC and EC to local BBP. Results were corrected for multiple comparisons and deemed significant at alpha 0.05. Results The peritumoral area was significantly more active than the non-peritumoral homologue in patients, and showed pathologically higher activity in comparison to HCs. Pathologically high neuronal activity was restricted to the peritumoral areas and not found in the contralateral homologue. However, patients’ functional network was disturbed throughout the brain in terms of pathologically high clustering, but not with regards to centrality. Whereas high activity related to high centrality in HCs and patients alike, high activity seemed to relate to low clustering in homologue regions in patients but not HCs, potentially indicating that lower neuronal activity relates to pathologically high clustering in these patients. Conclusion Glioma patients show pathologically high brain activity around the tumor and whole-brain disturbances in local network clustering, while integrative connectivity is preserved. We also find that the relationship between neuronal activity and functional network properties is complex in these patients, further underlining the importance of investigating how local activity may impact global network topology in order to understand how neuron-glioma interactions shape brain functioning.
PL01.3.A Radiomic features and DNA methylation attributes in primary CNS lymphoma
Authors: K Nenning, J Gesperger, A Nemc, T Roetzer-Pejrimovsky, S Choi, M Preusser, D Nam, C Bock, G Langs, A Woehrer
Journal: Neuro-Oncology (2022)

Abstract Background Clinical and laboratory markers have been exploited to model risk in patients with primary CNS lymphoma (PCNSL), but the derived risk models do not fully explain the observed variation in outcome. Here we present an extended framework of phenotype-epigenotype correlations that reveal novel prognostic constellations and enable prioritizing epigenetic therapy. Material and Methods In this retrospective discovery and validation study, we leverage radiomic feature-driven analysis of medical images and supervised bioinformatic integration of DNA methylation profiles. We integrate both data modalities synergistically using machine learning-based prediction and cross-domain alignment. Ultimately, we validate the most relevant biological associations in tumor tissues and cell lines. Results We leverage a cohort of 191 patients across 9 sites in Austria and an external validation site in South Korea, and use T1-weighted contrast-enhanced magnetic resonance imaging to derive a radiomic risk score that consists of 20 mostly textural features. We determine the risk score as strong and independent predictive factor (multivariate HR=6.56), and confirm its prognostic value in an external validation cohort. Radiomic features align with DNA methylation sites in distinct, biologically meaningful ways, and radiomic risk is predictable from selected DNA methylation sites (AUC=0.78). Ultimately, gene-regulatory differences between radiomically-defined risk groups converge on bcl6 binding activity, which is posed as testable treatment strategy in a subset of patients. Conclusion The radiomic risk score is a robust and complementary predictor of survival and is reflected at the level of DNA methylation in PCNSL. Assessing risk and selecting epigenetic treatment based on imaging phenotypes represents a huge step forward, and the ability to define radiomic risk groups provides a concept on which to advance prognostic modeling and precision therapy for this aggressive brain cancer.
P01.08.A Perioperative Levetiracetam for seizure prophylaxis in seizure naive brain tumor patients with focus on neurocognitive functioning
Authors: E Konrath, F Marhold, W Kindler, F Scheichel, B Popadic, K Blauensteiner, B Calabek-Wohinz, E Freydl, M Weber, R Ristl, K Hainz, C Sherif, S Oberndorfer
Journal: Neuro-Oncology (2022)

Abstract Background In seizure-naive brain tumor patients, the efficacy of perioperative prophylactic antiepileptic drugtreatment remains controversial. In case of administration, the common preferred drug is levetiracetam (LEV) because of its favorable pharmacological profile. Research to date has not sufficiently determined how LEV affects cognition in the short term as it does in the perioperative period. The objective of this prospective study was to examine the neurocognitive functioning of seizure-naive brain tumor patients after receiving LEV perioperatively. Material and methods Patients with supratentorial brain tumor undergoing surgery received LEV three days before until seven days after surgery as seizure prophylaxis. Cognitive functioning (NeuroCogFX), LEV plasma-levels, hematotoxicity, side-effects, as well as health-related quality of life (HRQoL, Qolie31), were recorded preoperatively before (Baseline) and after onset of LEV (Pre-Op), 4-6 days postoperatively (Post-Op) and 21 days postoperatively (Follow-Up). Results No significant changes in cognitive functioning and HRQoL were seen after onset of preoperative LEV. There was a significant improvement of NeuroCogFX total-score at Follow-Up (p=0.004) compared to Baseline. The overall-score Qolie31 showed simultaneous improvement patterns as cognitive functioning (p&amp;lt; 0.001). The most frequent side effect related to study drug was somnolence (in 24% of patients). Conclusion Following LEV therapy, a significant improvement of cognitive functioning, as well as an improvement in HRQoL, were detected postoperatively. This is presumably due to the debulking effect of the surgery. Nevertheless, LEV has no detrimental effect on cognitivefunctioning in the perioperative phase in seizure-naive brain tumor patients.
PL02.4.A International validation study of an EORTC instrument measuring instrumental activities of daily living (IADL) in patients with brain tumours: EORTC IADL-BN32
Authors: Q Oort, J Koekkoek, N K Aaronson, F W Boele, C Brannan, A Capela, M Hjermstad, M Klein, I Lips, Y Narita, A Pace, D Petranovic, J Pichler, J C Reijneveld, H Sato, C Seidel, O Shamieh, S A M Sikkes, A Talacchi, B M J Uitdehaag, T Urbanic, T Young, M J B Taphoorn, L Dirven
Journal: Neuro-Oncology (2022)

Abstract Background Brain tumour patients often have neurocognitive deficits which can result in problems with activities in daily living that are cognitively complex. Currently, no valid and reliable brain tumour-specific instrument to measure these instrumental activities of daily living (IADL) is available, but such an instrument is being developed. This study aimed to validate the EORTC IADL-BN32 questionnaire, comprising five multi-item and two single item scales, in a large set of international brain tumour patients. Material and Methods This international study was conducted in 10 countries worldwide. Primary and metastatic brain tumour patients and their proxies were requested to complete the EORTC IADL-BN32 and a subjective cognitive questionnaire (MOS COG-R) at multiple time points. Several psychometric properties were evaluated with baseline data, including the structural validity (bi-factor confirmatory factor analysis [CFA]), reliability (internal consistency), construct validity (known groups comparisons) and patient-proxy congruency (intra-class correlation coefficients [ICC], Spearman's correlation). Results At baseline, 326 patients ( 30% low-grade glioma, 37% high-grade glioma (HGG) and 33% brain metastases) and 311 proxies completed the EORTC IADL-BN32. The bi-factor CFA was found to have a satisfactory model fit (CFI=0.92 and TLI=0.90), and other parameters indicated a good fit (RMSEA=0.08 and SRMR=0.05), thereby validating the preliminary scale structure, but also an IADL sum score. The multi-item scales showed good (0.9&amp;gt;α≥0.8) to excellent (α≥0.9) internal consistency (range α=0.86-0.97). Known groups comparisons analyses regarding patient’s cognitive status (indications vs. no cognitive impairment), subjective cognitive complaints (MOS COG-R ≤30 vs. &amp;gt;30), basic ADL (Barthel Index &amp;lt;100 vs. 100) and performance status (KPS &amp;lt;70 vs. ≥70) showed significant differences on all IADL outcome measures in line with a priori defined hypotheses. On a group level, patient and proxy ratings had moderate to strong correlations, however, proxies tended to report more problems on all scales. The ICCs showed moderate to good congruency between patients and proxies (range ICC: 0.63-0.81). Conclusion The evaluated psychometric properties support the current scale structure of the EORTC IADL-BN32. Additional psychometric properties with longitudinal data are needed, such as test-retest reliability and responsiveness, to further validate the EORTC-IADL BN32 questionnaire.
OS07.1.A A threshold of mitotic activity and post-surgery residual volume are independant prognostic factors in astrocytoma IDH-mutant
Authors: S Tran, A Thomas, M Touat, C Karachi, F Lozano, K Mokhtari, C Dehais, L Feuvret, C Carpentier, M Giry, H Doukani, J Lerond, Y Marie, M Sanson, A Idbaih, A Carpentier, K Hoang-Xuan, L Capelle, F Bielle
Journal: Neuro-Oncology (2022)

Abstract Background The distinction between grade 2 and 3 is instrumental to choose between observational follow-up and adjuvant treatment in resected astrocytoma IDH-mutant. However, criteria of grade 2 versus 3 have not been updated since the WHO 2007 classification. There is no consensus on the method of evaluation of the mitotic activity or a cut-off of mitoses separating grade 2 and grade 3 tumors. The objectives were to evaluate the maximal mitotic activity on a series of resected astrocytoma IDH-mutant and assess its prognostic impact on survival. Material and Methods Maximal mitotic activity on consecutive high power fields corresponding to 3 mm2 was examined in 118 lower-grade astrocytoma IDH-mutant. The prognostic value for time-to-treatment (TTT) and overall survival (OS) of mitotic activity and other putative prognostic factors (including age, performance status, pre-surgical tumor volume, plurilobar involvement, post-surgical residual tumor volume, midline involvement) was assessed in tumors with (i) ATRX loss, and (ii) without CDKN2A homozygous deletion, lesional enhancement, histological necrosis nor microvascular proliferation. Results Among the 75 (64%) of tumors which had gone through observational follow-up after resection, the maximal mitotic activity, the post-surgical residual volume and the plurilobar involvement were independent prognostic factors of TTT (p &amp;lt; 0.0001). A threshold of mitotic activity for grade 2 was fitted on TTT and OS prognosis. Using this threshold, patients with “grade 2 tumors” had a median TTT of 55 months versus 19 months for “grade 3” (p = 0.0057) and a median OS of 102 months versus 73 months respectively (p = 0.001). Residual volume &amp;lt; 1 cm3 was associated with longer OS (113 months versus 88 months, p = 0.0021). Conclusion Mitotic activity and post-surgical residual volume can be combined to evaluate prognosis in resected astrocytoma IDH-mutant and could select the best candidates for observational follow-up.
P01.11.A Perioperative executive functioning in patients with low-grade gliomas near the Frontal Aslant Tract
Authors: M J F Landers, E Butterbrod, W De Baene, M M Sitskoorn, G M Rutten
Journal: Neuro-Oncology (2022)

Abstract Background A tract potentially involved in important executive cognitive processes is the Frontal Aslant Tract (FAT). In particular the right FAT has been associated with executive functioning (EF). In neurosurgery, it remains unclear if patients with tumors near the FAT demonstrate EF impairments after resection. This study investigated whether low grade gliomas (LGG) that affect the core white matter and/or structural integrity of the FAT predict preoperative and 3 months postoperative EF, when controlled for tumor volume and the integrity of other nearby tracts (SLF II and SLF III). Material and Methods Data was analyzed from patients with frontal and parietal LGG who underwent surgery between 2010-2021. Probabilistic tractography was performed prior to surgery to generate preoperative tracts of the FAT, SLF II and SLF III. The core of the FAT was defined as the white matter between the seed and the target region. Average mean diffusivity for each tract was taken as a measure of structural integrity. EF was assessed one day before and 3 months post-surgery with the following tests: Stroop test, symbol digit coding test (SDC), shifting attention test (SAT), and letter fluency test (LF). We performed linear mixed models and linear regression analyses to investigate the relationship between presurgical tumor overlap with the core of the FAT and FAT integrity with pre- and postsurgical executive test performances. Results Seventy-five patients were included (left tumor N=39, right tumor N=36). Mean pre-surgical Z-scores were within 0.5 standard deviation from a healthy control group for all tests, but with substantial variance between patients (Z-score range:-3.59 to 2.4). The results demonstrated that core overlap of the right FAT predicted preoperative performance on the SAT (p&amp;lt;.01, β= -.473), Stroop (p&amp;lt;.01, β= -.519), and SDC (p&amp;lt;.01, β= -.519). Right or left core overlap did not significantly predict performance three months after surgery. FAT integrity did not predict preoperative EF performance, whereas it did predict SAT performance at three months post-surgical (p&amp;lt;.01, β= -.694) when controlled for SLF II, III integrity and tumor volume. Conclusion Although patients with frontal or parietal LGG showed no dysfunction on tests of EF before surgery on group level, they demonstrated large variability between patients. Tumor overlap with the core of the right FAT predicted worse presurgical EF performances, but not short-term post-surgical performances. Right FAT integrity predicted short-term post-surgical performance on cognitive flexibility. These results are in line with previous findings that the right FAT is involved in EF and indicate that preoperative FAT integrity might predict which patients will perform worse after surgery.
P03.09.A Proton beam therapy for adults medullobastoma
Authors: R Frakulli, N Ni, L Schmidt, F Guntrum, P Kramer, S Frisch, M Glas, B Timmermann
Journal: Neuro-Oncology (2022)

Abstract Background Although Medulloblastoma (MB) is the most common primary malignant intracranial tumor in childhood, in adults it is extremely rare. Therefore, available data is scarce and experience with radiation and proton beam therapy (PBT) is very limited. The treatment typically includes tumour resection, irradiation of the craniospinal axis (CSI) followed by a boost, +/- concomitant chemotherapy, and maintenance therapy. Herein, we present our preliminary analysis of outcome and toxicity after PBT. Material and Methods Patients ≥ 18 years with primary MB treated with PBT between January 2017 and March 2020 enrolled in the prospective registry study (DRKS00004384) were evaluated in this analysis. Within the registry, adverse events were documented according to CTCAE v4.0 before, during, and after PT. The overall survival (OS), local control (LC) and higher-grade toxicity (≥ grade 3) were analyzed. Results A total of 19 patients (13 males, 6 females) with a median age of 23 years (range, 18.5- 39 years) were included in this study. Histopathology type were classic, desmoplastic /extensive nodularity or anaplastic MB in 52.6%, 26.3% and 21.1 % of patients, respectively. Complete tumor resection was performed in 57.8 % of patients. 68.4 % of patients had local disease without any metastases. Median total CSI dose was 35.2 Gy(RBE) (range, 23.4-40 Gy) with a median single dose of 1.6 Gy(RBE) (range, 1-1.8 Gy). All patients received either boost to the posterior fossa (57.9%) or to the tumor bed only (42.1%). The median total tumor dose was 18.8 Gy(RBE) (range, 54-68 Gy). Concomitant chemotherapy was given to 63.1% of patients. The median follow-up time after first diagnosis was 28.2 months (range, 8-56 months). No higher-grade acute or late adverse event was documented so far. One patient developed local disease progression. Another patient deceased due to an acute pulmonary embolism during maintenance chemotherapy without evidence of disease. The 3-year LC and OS rate were 89 % and 94 %, respectively. Conclusion Early results display good feasibility and high tumor control of PT in adult patient with MB. Results will need to be confirmed in larger cohort with longer follow-up time.&amp;lt;Bookmark(28)&amp;gt;